Carotenoid compounds are characterized by the conjugated polyene chains, and some of the representative examples are β-carotene, lycopene, and astaxanthin etc. β-Carotene have found not only the industrial applications as animal feeds and colorants for foodstuffs but also the medicinal applications due to its prophylaxis effects on certain cancers by selectively reacting with cancer suspects such as singlet oxygen and radicals. Therefore, β-carotene has been widely utilized as food additives and nutraceuticals.
One of the representative synthetic methods of β-carotene is delineated in Scheme 1, which has been the commercial process of Hoffmann-La Roche (Isler, O; Lindlar, H.; Montavon, M.; Ruegg, R.; Zeller, P. Helv. Chim. Acta 1956, 39, 249-259). The key of the process is the coupling reaction of two moles of the C19 units with one mole of bis-magnesium acetylide. Partial hydrogenation of the coupled C40 diol, followed by dehydration under an acidic condition then produced β-carotene. According to the above Roche process, it required two consecutive condensation reactions with enol ethers to prepare the C19 unit from the C14 aldehyde. The above non-convergent and length steps, not to mention of the stereochemical issue of the polyene chain, made the process less practical.

The second representative synthetic method of β-carotene, which was adopted by BASF as a commercial route, is described in Scheme 2, in which the Wittig reaction of two moles of the C15 phosphonium salt and one mole of the C10 dialdehyde produced β-carotene (Wittig, G.; Pommer, H. German Patent 954,247, 1956). This process was composed of short reaction steps, and efficiently formed the conjugated polyene chain by the Wittig reaction. However, there is a major problem in the purification of β-carotene from phosphine oxide (Ph3P═O), the byproduct of the Wittig reaction.

To overcome the afore-mentioned problems, we recently developed the practical synthetic method of β-carotene, which was composed of relatively short steps and had a strong advantage in the purification of β-carotene from a byproduct in the formation of the conjugated polyene chain (Koo, S.; Choi, H.; Ji, M.; Park, M. WO 00/27810; Koo, S.; Yang, J.-D.; Kim, J.-S.; Lee, S.; Park M. WO 03/037,854). This process utilized the Julia coupling reaction of two moles of the C15 allylic sulfone compound and one mole of the C10 dihalide compound to construct the required C40 carbon skeleton. The Ramberg-Bäcklund reaction of the central allylic sulfone moiety to give the conjugated triene, followed by dehydrosulfonylation reactions produced β-carotene containing the fully conjugated polyene chain (Scheme 3).

The above sulfone-mediated process for β-carotene has several advantages over the other methods. The stable intermediates are formed through the process, which can be easily purified by recrystallization. Biologically more active all-(E)-β-carotene can be produced stereoselectively in the dehydrosulfonylation process. However, there is a crucial disadvantage in the above process. The formation of the central conjugated triene unit of E-configuration by the Ramberg-Bäcklund reaction was not a trivial transformation, which gave less than 70% yield of the desired product with a significant amount of the (Z)-isomer. It was thus instantly requested to devise a better synthetic method of β-carotene with practical and economical values based on the Julia sulfone-mediated coupling and olefination protocol not going through the Ramberg-Bäcklund reaction to overcome the above disadvantage.